Columbia University Medical Center Researchers Evaluate New Therapy

New York, NY(Apr 29, 2003)

A drug used with great success to enhance fertility in women may also play a new role for the opposite sex-increasing low testosterone levels in men. The drug, clomiphene citrate (commonly known as Clomid*), is currently under study by researchers at the Male Reproductive Center at Columbia University Medical Center at NewYork-Presbyterian Hospital, as an alternative to currently available treatment options (which while effective, can cause multiple complications).

Results of a preliminary study were announced today, April 29, 2003, at the American Urological Association Annual Meeting in Chicago.

The results of our pilot study of clomiphene citrate indicate that it may have a significant new application. We've been able to show that it is very effective in raising male testosterone levels without the side effects usually associated with current therapies for this condition, says Harry Fisch, MD, director of the Center and associate clinical professor of urology at Columbia University College of Physicians & Surgeons.

Declining testosterone levels can cause problems for many men as they age. Coupled with an increase in estrogen levels, this change in sex hormone levels may result in adverse effects on libido, sexual function, mood and behavior (such as depression, fatigue, irritability, memory loss, decrease in intellectual activity), lean body mass, and bone density, as well as the development of diabetes, weight gain, and muscle weakness.

It is known that average serum testosterone levels decrease by 1 percent per year after age 40; hypogonadism is detected in 20 percent of men older than 60 years. Hypogonadism in aging males affects over 5 million Americans. This decrease in testosterone production, or hypogonadism, in aging men is a combination of hypothalamus-pituitary axis dysfunction and testicular dysfunction with a consequent decreased production of testosterone. Luteinizing hormone (LH) levels in these men frequently are within the normal range despite low testosterone levels, which indicates potential hypothalamic-pituitary dysfunction rather than primary testicular failure (abnormal high LH levels are associated with primary testicular failure).

Clomiphene citrate is a weak estrogen receptor antagonist that competes with estradiol (the most potent of the naturally occurring estrogens produced by both men and women) for the estrogen receptors at the level of the hypothalamus (the drug was recently reclassified as a selective-estrogen receptor-modulator [SERM] because of this ability). It blocks the normal negative feedback of circulating estradiol on the hypothalamus, which prevents estrogen from limiting the production of gonadotropin-releasing hormone (GnRH). The resulting increase in GnRH level then stimulates the pituitary gland to release more follicle-stimulating hormone (FSH) and LH, resulting in increased sperm and testosterone production by the testes.

Current treatment options for this type of hypogonadism in men are limited to testosterone supplementation via gels, patches, or intramuscular injections. These treatments can be associated with multiple side effects such as skin irritation, abnormally increased breast size, nipple tenderness, testicular atrophy, and sperm count decline. Testosterone pills have been used in Europe and have been associated with liver and gastrointestinal dysfunction.

Because of the combination of hypothalamus-pituitary axis dysfunction and testicular dysfunction seen in these men and because of the adverse effects of current therapies, we decided to explore means of causing the body to make more testosterone itself, rather than add testosterone to it from an outside source, explains Dr. Fisch. The increase in testosterone would then be accomplished without side effects, he adds.

The Columbia study evaluated the use of clomiphene citrate tablets in 36 Caucasian men with hypogonadism, which was defined as a serum testosterone level 300 ng/dl. Each patient received a daily dose of 25 mg of clomiphene citrate. The average patient age was 39 years, with 12 over age 40. The average pretreatment testosterone level was 247.6 ng/dl. All patients received the drug for at least three months; the entire group was followed for 1 year.

By the first follow-up visit, which occurred between four and six weeks of the start of therapy, the average testosterone level rose to 610 ng/dl, an increase of 146 percent compared with baseline. This response was seen in all patients regardless of age.

No patients reported any of the known side effects of clomiphene citrate, such as hot flashes, visual disturbances, or headaches. In fact, most patients reported improvements in overall well-being, sex drive, physical strength, and mood on follow-up visit interviews. Some experienced these changes in as little as three months of therapy, points out Dr. Fisch.

According to Dr. Fisch, this preliminary study revealed some promising results. We've been able to show that clomiphene citrate induces internal production of testosterone via blockage of the hypothalamic estrogen receptor. This effect presents a unique therapeutic opportunity for the management of hypogonadism in aging men. Low-dose oral therapy with minimum side effect may prove to be an excellent substitute to transdermal or injectable testosterone alternatives. However, further investigation is needed, as well as phase II studies that will determine the optimal dose for different age groups. And methodical measurements of muscle strength, weight, sexual function, exercise tolerance, bone density, and mood changes are required before accepting this drug as a standard of care for hypogonadism, he concludes.